Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, monocytes, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils. The chemokines and their cognate receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and arthrosclerosis (reviewed in: Carter, P. H., Current Opinion in Chemical Biology, 6:510 (2002); Trivedi et al., Ann. Reports Med. Chem., 35:191 (2000); Saunders et al., Drug Disc. Today, 4:80 (1999); Premack et al., Nature Medicine, 2:1174 (1996)). For example, the chemokine macrophage inflammatory protein-1 (MIP-1α) and its receptor CC Chemokine Receptor 1 (CCR-1) play a pivotal role in attracting leukocytes to sites of inflammation and in subsequently activating these cells. When the chemokine MIP-1α binds to CCR-1, it induces a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of leukocyte migration.
In addition, demonstration of the chemotactic properties of MIP-1α in humans has been provided experimentally. Human subjects, when injected intradermally with MIP-1α, experienced a rapid and significant influx of leukocytes to the site of injection (Brummet, M. E., J. Immun., 164:3392-3401 (2000)).
It is known that MIP-1α is elevated in the synovial fluid and blood of patients with rheumatoid arthritis. Moreover, several studies have demonstrated the potential therapeutic value of antagonism of the MIP-1α/CCR1 interaction in treating rheumatoid arthritis.
It should also be noted that CCR-1 is also the receptor for the chemokines RANTES, MCP-3, HCC-1, Lkn-1/HCC-2, HCC-4, and MPTP-1 (Carter, P. H., Curr. Opin. Chem. Bio., 6:510-525 (2002)).
Recently, inhibitors of CCR-1 that may be useful in the treatment of inflammatory disorders have been discovered. In particular, Compound I of the formula
is disclosed in US 2009/0326010 A1 (assigned to Applicant) which published on Dec. 31, 2009. This compound is highly crystalline, non-ionizable in a pH range of 2-11, and has low aqueous solubility at room temperature. Suspensions of compound I, including nanosuspensions, have demonstrated unacceptable bioavailabilities in rats.
Solid dispersion systems of amorphous drug have been investigated with the objective of inhibiting crystal growth and enhancing the dissolution of poorly water soluble drugs. See, e.g., European Journal of Pharmaceutics and Biopharmaceutics, 63:103-114 (2006). Generally, it has been found that effective solid amorphous dispersions require the incorporation of at least 20% w/w or higher of polymers (see e.g., WO 10/102,245 A and US 2003/0219489). In one instance it was reported that 5% w/w of PVP may inhibit the crystal growth of indomethacin in a molecular dispersion, reportedly via hydrogen bonding of the active ingredient with the PVP polymer. See Pharmaceutical Research, 16:1722-1728 (1999). Also, polymer formulations of antihelmintics have been disclosed that exhibit increased solubility and anthelmintic activity. See EP 0 224 249.
What is therefore now needed in the art is one or more bioavailable amorphous formulations of Compound I that are stable, have a desirable pharmaceutical profile, and are amenable to manufacturing conditions.